Kinin B1 receptors as a therapeutic target for inflammation

ABSTRACT

Introduction: Kinins are peptide mediators exerting their pro-inflammatory actions by the selective stimulation of two distinct G-protein coupled receptors, termed BKB1R and BKB2R. While BKB2R is constitutively expressed in a multitude of tissues, BKB1R is hardly expressed at baseline but highly inducible by inflammatory mediators. In particular, BKB1R was shown to be involved in the pathogenesis of numerous inflammatory diseases.

Areas covered: This review intends to evaluate the therapeutic potential of substances interacting with the BKB1R. To this purpose we summarize the published literature on animal studies with antagonists and knockout mice for this receptor.

Expert Opinion: In most cases the pharmacological inhibition of BKB1R or its genetic deletion was beneficial for the outcome of the disease in animal models. Therefore, several companies have developed BKB1R antagonists and tested them in phase I and II clinical trials. However, none of the developed BKB1R antagonists was further developed for clinical use. We discuss possible reasons for this failure of translation of preclinical findings on BKB1R antagonists into the clinic.

KEYWORDS:

• B1 receptor
• B2 receptor
• bradykinin
• carboxypeptidase M
• des-Arg⁹-bradykinin
• des-Arg¹⁰-kallidin
• inflammatory diseases
• kallidin
• kallikrein-kinin system
• kinins
• kininogen
• plasma kallikrein
• tissue kallikrein

Article highlights

• Kinin B1 receptors (BKB1R) are mainly expressed at sites of inflammation and therefore potentially safe drug targets for inflammatory diseases

• BKB1R antagonism and gene deletion has been shown to be beneficial in numerous animal models of inflammatory diseases, with few exceptions.

• Several companies have developed orally available BKB1R antagonists

• Some BKB1R antagonists went into phase II clinical trials, but none was developed further into the clinic

• Possible reasons for this failure may be inefficiency in humans due to species differences, or human specific adverse effects

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.